Certain transition metals like nickel (Ni), chromium (Cr), and cadmium (Cd), are carcinogenic to humans, especially in the industrial environment (e.g., metallurgy and welding); however, the mechanisms of their carcinogenic activity remain obscure. In recent years, we have formulated a novel hypothesis that one such mechanism would involve metal-mediated oxidative damage to DNA and nuclear proteins. By testing that hypothesis, we revealed previously that the metals did, indeed, induce DNA base damage in vitro and in vivo in a way typical for oxygen radical attack. In 1994/ 95 our in vitro studies have focused on nickel interactions with histone H3, which contains a conserved motif with high affinity for transition metals. The model peptide of this motif, CH3CO-Cys- Ala-Ile-His-NH2 (L), was synthesized and its reactions with nickel(II) [Ni(II)] evaluated, using physicochemical techniques. At pH 7.4, two macrochelate square planar complexes, Ni(II)L and Ni(II)L2, were formed, with the metal cation bound through Cys and His side chains. These complexes were sensitive to autoxidation, yielding L dimer and other products. UV/vis spectra typical for Ni(II)-L binding were also found in mixtures of Ni(II) and histone tetramer (H3H4)2. The Ni(II)-L complexes catalyzed oxidation of 2'-deoxyguanosine (dG) to promutagenic 8-oxo-dG. Thus, the binding of Ni(II) by L in histone H3 and redox catalysis by the resulting complexes may damage both the histone and the nucleic acid in chromatin; that, in turn, may alter the fidelity of DNA replication and/or gene expression. In our in vivo experiments, mice of C3H, C57BL, and B6C3F1 strains, differing in antioxidant levels in their tissues, were tested for susceptibility to lethal and carcinogenic effects of nickel subsulfide (Ni3S2). The lethality ranking, C57BL > B6C3F1 > C3H, reflected the increasing antioxidant capacity of liver and kidney, targets for nickel toxicity. In contrast, tumor yield, C3H > B6C3F1 > C57BL, was high in mice with relatively lower antioxidant capacity in their muscles, the target for Ni3S2 carcinogenicity. These results stress the importance of redox mechanisms to nickel toxicity and carcinogenesis. Our work yields data supporting the oxidative damage hypothesis and provides an experimental basis for collaborative studies on such damage in perinatal and bacterial carcinogenesis (see Z01CP05352-13 and Z01CP05301-14).